Amphetamine Sensitization Alters Dendritic Morphology in Prefrontal Cortical Pyramidal Neurons in the Non-Human Primate

Abstract

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3 1 2 years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.3877.65 mm in AMPH-sensitized compared to 162.9877.26 mm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia. Neuropsychopharmacology (2007) 32, 919-931.

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats

“…Postmortem reports have described no gliosis, but a high Bax / Bcl-2 ratio with a normal caspase 3 level in chronic schizophrenia, implying that an apoptotic process in the chronic patients plays an important role in progressive cortical atrophy from prodrome to several years after the first psychotic episode in schizophrenia [10,15]. Smaller somal volume and decreased spine density, dendritic length, and terminals than in normal controls, which are seen in schizophrenia [10], are similarly induced in high-dose amphetamine-induced sensitized animals [29]. A toxic dosage regimen of METH induces apoptosis in cortical neurons in the medial prefrontal cortex (mPFC) [17].…”

Mechanisms of Psychostimulant-Induced Structural Plasticity

“…It is worth mentioning that nonhuman primate studies using Rhesus macaques show that both experimenteradministered and self-administered amphetamine significantly decreased mPFC dendritic spine density (Selemon et al 2007;Coutinho et al 2008). This dichotomy is interesting, although significant differences exist between the drug regimens and withdrawal period between these species-divergent studies and warrant further investigation (Table 1).…”

Neonatal Phencyclidine Treatment in Mice Induces Behavioral, Histological and Neurochemical Abnormalities in Adulthood

“…Spontaneous Locomotor Activity PCP-treated mice were subjected to the behavioral experiment at postnatal weeks [15][16][17][18][19]. The animals were housed individually in plastic cages (W-D-H: 215ϫ320ϫ140 mm) and acclimatized for 3 d before the measurement of spontaneous locomotor activity.…”

“…In the nucleus accumbens and striatum, spiny neurons were selected. A criterion for selecting nerve cells was established as described below using a modified method described by Selemon et al 17) : nerve cells, at least 3 dendrites of which extended centrifugally from the soma.…”